Bis-(α-amino)-diol-diester-containing poly (ester amide) and poly (ester urethane) compositions and methods of use

ABSTRACT

The present invention provides biodegradable, biocompatible bis-(α-amino acyl)-diol-diester-containing poly(ester amide) (PEA) and poly(ester urethane) (PEUR) co-polymer compositions with mechanical properties that can be readily tailored by selection of various combinations and proportions of the building blocks of the co-polymers. The compositions are suitable for use in production of drug-releasing biodegradable particles and implantable surgical devices, such as stents and internal fixation devices. The co-polymer compositions, particles and surgical devices biodegrade in vivo by enzymatic action to release bioactive agents in a controlled manner over time as well as biocompatible breakdown products, including one to multiple different amino acids.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.12/066,998, filed Jul. 31, 2008, which is the National Stage Entry ofInternational Application No. PCT/US2006/037331, filed Sep. 22, 2006,which claims the benefit of U.S. Provisional Patent Application No.60/839,219, filed Aug. 21, 2006, and U.S. Provisional Patent ApplicationNo. 60/719,950, filed Sep. 22, 2005. The entire contents of theabove-identified applications are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates, in general, to drug delivery systems and, inparticular, to polymer delivery compositions that incorporate aliphaticamino acids into a biodegradable polymer backbone.

BACKGROUND INFORMATION

The earliest drug delivery systems, first introduced in the 1970s, werebased on polymers formed from lactic and glycolic acids. Today,polymeric materials still provide the most important avenues forresearch, primarily because they are easy to process and researchers canreadily control their chemical and physical properties via molecularsynthesis. Basically, two broad categories of polymer systems, bothknown as “microspheres” because of their size and shape, have beenstudied: reservoir systems and matrix systems. The former involves theencapsulation of a pharmaceutical product within a polymer shell;whereas the latter describes a system in which a drug is physicallyentrapped or matrixed within a polymer network.

The release of medications from either category of polymer systemtraditionally has been diffusion-controlled. Currently, however, modernresearch is aimed at investigating biodegradable polymer systems. Thesedrug deliverers, for example polyhydoxyalkanoates, degrade intobiologically acceptable compounds, often through the process ofhydrolysis, and leave their incorporated medications behind. Thiserosion process occurs either in bulk (wherein the matrix degradesuniformly) or at the polymer's surface (whereby release rates arerelated to the polymer's surface area). The degradation process itselfinvolves the breakdown of these polymers into lactic and glycolic acids.These acids are eventually reduced by the Kreb's cycle to carbon dioxideand water, which the body can easily expel.

Amino Acid based Bioanalogous Biopolymers (AABB)—a new family ofhydrophobic α-amino acid based polymers—recently has been developed.Poly(ester amides), (PEAs) and poly(ester urethanes) (PEURs) with linearstructures, which are based on essential α-amino acids, fattydicarboxylic acids and aliphatic diols have been synthesized via anActive Polycondensation (APC) method. The APC method mainly is conductedin solution under mild temperatures without use of any toxic catalyst.Using this method, a large variety of AABB polymers with a broad rangeof physical and thermo-mechanical properties and biodegradation profileshave been reported and studied. See review paper and references thereinby R. Katsarava (Macromol. Symp. (2003) 199:419-429).

In particular, amino acid-based poly(ester amide) (PEA) and poly(esterurethane) (PEUR) polymers demonstrate enzyme-mediated surfacedegradation (G. Tsitlanadze, et al. J. Biomater. Sci. Polym. Edn. (2004)15:1-24) and a low inflammation profile (K. DeFife et al. TranscatheterCardiovascular Therapeutics—TCT 2004 Conference. Poster presentation.Washington D.C. (2004)). These properties make PEAs and PEURs excellentmaterials for a variety of different medical and pharmaceuticalapplications.

Another significant advantage of the APC method is that PEAs and PEURswith programmed physical and mechanical properties as well asbiodegradable profiles can be achieved simply by varying threecomponents in the building blocks during their synthesis: naturallyoccurring amino acids and, therefore, hydrophobic α-amino acids,non-toxic fatty diols and aliphatic dicarboxylic acids. From thesecomponents, the following building blocks are built and subjected to theAPC method: nucleophilic monomers of bis-(α-amino acid)-α,ω-alkylenediesters and bis-electrophiles, which are activated esters of di-acids,for example, bis-(p-nitrophenyl) diesters of fatty di-acids.

Recently, a series of new unsaturated biodegradable PEAs also have beenreported, wherein two different types of unsaturation can be introducedinto the main backbone: naturally occurring fumaric acid as a di-acidcomponent or 2-butene-1,4-diol-diester as an unsaturated diol partner(K. Guo, et al. Synthesis and Characterization of Novel BiodegradableUnsaturated Poly(ester-amides). J. Polym. Sci: Part A: Polym. Chem.(2005) 43:1463-1477). These unsaturated PEAs, particularly polymersbased on fumaric acid, showed poor solubility in most organic solvents,high glass transition temperatures in the range of 96° C.-109° C., andsharp melting endotherms in the range of 220° C.-250° C., a thermalprofile of that also can be interpreted as indicating simultaneousthermal crosslinking of the polymers.

The physical properties of PEAs and PEURs are heavily dependent on thestructure of the polymer backbone, as shown in recent works (KatsaravaR, et al. J. Polym. Sci: Part A: Polymer Chemistry, 37, 391-407 (1999)and U.S. Pat. No. 6,503,538 B1). For example, replacement of aliphaticdiols in the backbone with bicyclic rigid fragments of“sugar-diols”—1,4:3,6-dianhydrohexytols has been shown to significantlyincrease the glass transition temperature (Tg) of PEAs, providing aglass transition temperature as high as 103° C., while esterase-mediateddegradation rates remained in the same order of magnitude as those forother PEAs and PEURs (Z. Gomurashvili, et al. J. Macromol. Sci. PureAppl. Chem. (2000) A37:215-227 and M. Okada et al. J. Appl. Polym. Sci.(2001) 81:2721-2734). However, the sugar-diol containing PEAs of thisstudy tend to be unduly rigid.

Thus, there is a need in the art for more and better varieties ofbiocompatible polymer compositions and methods for deliveringtherapeutic molecules, such as drugs and other bioactive agents, at acontrolled rate of therapeutic or palliative release, while affordingenhanced mechanical and physical properties.

SUMMARY OF THE INVENTION

The present invention is based on the discovery of new bis-(α-aminoacid)-diol-diester based PEA and PEUR co-polymer compositions containingtwo bis-(α-amino acid)-based building blocks with significantimprovement in mechanical properties. Bis-(α-amino acid)-diol-diester isa type of diamine monomer, useful for active polycondensation (APC), andwhich inherently contains two aliphatic ester linkages. Such estergroups can be enzymatically recognized by various esterases.Condensation of diamine monomers, for example, with activated di-acidesters, results in a PEA macromolecule with ester and amide linkages.Incorporation of a bicyclic-fragment of 1,4:3,6-dianhydrohexitol as thediol residue in at least one of the two bis(α-amino acid)-based buildingblocks in the invention polymers confers high glass transitiontemperature (Tg) on the polymer. Incorporation of at least two linearsaturated or unsaturated aliphatic diol residues into the two bis-(αamino acid)-based (e.g. bis-(α-amino acid)-diol-diester co-monomers of aPEA), increases the elongation properties of the resulting polymer.Analogously, if at least one of the di-acid residues in the co-polymeris an unsaturated diacid, an increase occurs in the Tg due to polymerself-cross-linking. Similarly, the invention PEUR co-polymers are basedon judicious selection of the diol residues used for polycondensationwith the bis-(α-amino acid) diester building blocks suitable for a PEUREU to provide enhanced mechanical properties to the polymers. Inaddition, the invention PEA and PEUR co-polymer compositions optionallycan include a third monomer that is based on a C-protected adirectionalamino acid monomer to introduce additional flexibility into the polymerand to afford a pendent group suitable for covalent attachment of abioactive agent, if desired.

Thus the invention provides new PEA and PEUR co-polymers suitable forcertain applications requiring a combination of hydrophobicity,relatively high glass transition temperature (Tg), and properties ofvariable elongation or flexibility. Moreover, since theoretically thebis-(α-amino acid)-diol-diester co-monomers in the invention PEA andPEUR co-polymers may each contain a different one of the multiple aminoacids disclosed herein in each bis-(α-amino acid) building block, theinvention PEA and PEUR co-polymer compositions break down, for examplein vivo, to produce from one to multiple different of such α-aminoacids.

More particularly, in one embodiment, the invention provides co-polymercompositions containing at least one or a blend of the following:

a PEA having a chemical structure described by general structuralformula (I):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and wherein n is about 5 to about 100; and

wherein R¹ is independently selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and combinations thereof; R³sand R⁴s in a single co-monomer m or p, respectively, are independentlyselected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl and —(CH₂)₂S(CH₃);R⁵ is selected from bicyclic-fragments of 1,4:3,6-dianhydrohexitols ofstructural formula (II); and

R⁶ is selected from the group consisting of (C₂-C₂₀) alkylene, (C₂-C₂₀)alkenylene or alkyloxy;

or a PEA having a chemical structure described by general structuralformula (III):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and q is about 0.99 to 0.01; and wherein n is about 5 to about 100; and

wherein R¹ is independently selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and combinations thereof; R³sand R⁴s in a single co-monomer m or p, respectively, are independentlyselected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl and —(CH₂)₂S(CH₃);R⁵ is selected from bicyclic-fragments of 1,4:3,6-dianhydrohexitols ofstructural formula (II); R⁶ is selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene or alkyloxy; R⁷ is hydrogen,(C₆-C₁₀) aryl (C₁-C₆) alkyl or a protecting group; and R⁸ isindependently (C₁-C₂₀) alkyl or (C₂-C₂₀) alkenyl;

or a PEUR having a chemical structure described by general structuralformula (IV):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and n is about 5 to about 100;

and wherein R² is selected from the group consisting of (C₂-C₂₀)alkylene, (C₂-C₂₀) alkenylene, and bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (III); the R³s and R⁴sin a single co-monomer m or p, respectively, are independently selectedfrom the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl, and —(CH₂)₂S(CH₃); R⁵ isselected from the group consisting of (C₂-C₂₀) alkylene, and (C₂-C₂₀)alkenylene or alkyloxy; R⁶ is selected from bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (II);

or a PEUR having a chemical structure described by general structuralformula (V):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01; qis about 0.99 to 0.01; and n is about 5 to about 100;

and wherein R² is selected from the group consisting of (C₂-C₂₀)alkylene, (C₂-C₂₀) alkenylene, and bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (II); the R³s and R⁴s ina single co-monomer m or p, respectively, are independently selectedfrom the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl, and —(CH₂)₂S(CH₃); R⁵ isselected from the group consisting of (C₂-C₂₀) alkylene, and (C₂-C₂₀)alkenylene or alkyloxy; R⁶ is selected from bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (II); R⁷ is hydrogen,(C₆-C₁₀)aryl (C₁-C₆) alkyl or a protecting group; and R⁸ isindependently (C₁-C₂₀) alkyl or (C₂-C₂₀) alkenyl.

In another embodiment, the invention provides methods for fixing aninternal body site in a subject by implanting into the internal bodysite of the subject an internal fixation device made using an inventionPEA or PEUR co-polymer composition. The device biodegrades to createsubstantially biocompatible breakdown products while fixing the internalbody site.

In yet another embodiment, the invention provides biodegradable,biocompatible surgical devices fabricated using an invention PEA or PEURco-polymer composition.

DETAILED DESCRIPTION OF THE INVENTION

The invention describes PEA and PEUR co-polymers based, respectively, ontwo bis-(α-amino acid)-diol-diester (diester-diamine) containingco-monomers with significant improvement in mechanical properties. Whileeach of the building blocks contributes to the properties of any givenPEA or PEUR co-polymer, in the present invention selection of the diolresidues in each of the three possible monomer units (including theadirectional amino acid-based monomer) is exploited to control themechanical properties of the co-polymers. Incorporation of abicyclic-fragment of a 1,4:3,6-dianhydrohexitol as the diol residue inat least one of the two diester-diamine based co-monomers confersrelatively high glass transition temperature (Tg) on the co-polymerwhile introduction of a residue of a saturated or unsaturated alkyl diolin each such co-monomer provides increased elongation properties of theresulting co-polymer (Table 1).

One or a mixture of at least two fatty dicarboxlyic acid residues linksthe two diester-diamines in the invention co-polymers. A thirdadirectional amino acid-based monomer optionally included in aninvention co-polymer contains an additional diol residue that can beselected to further control the mechanical properties of the co-polymeras well as providing a pendent group suitable for conjugation of abioactive agent. These new PEA and PEUR co-polymers exhibit acombination of hydrophobicity, relatively high glass transitiontemperature (Tg) to confer sufficient stiffness for the co-polymers tobe extruded, and also provide sufficient elongation properties toprevent brittleness. Each one of the individual monomer units in theinvention PEA and PEUR co-polymer compositions is based on and breaksdown during biodegradation to yield one of multiple different α-aminoacids, as disclosed herein.

Like other PEA and PEUR polymers, the invention PEA and PEUR co-polymercompositions can be used to deliver in vivo one or more bioactive agentsthat are dispersed in the co-polymer of the composition. The inventioncompositions biodegrade in vivo by enzymatic action at the surface ofthe co-polymer composition so as to release the one or more bioactiveagent(s) from the co-polymer in a controlled manner over time.

As used herein, the term “residue of a di-acid” means a portion of adicarboxylic-acid, as described herein, that excludes the two carboxylgroups of the di-acid. As used herein, the term “residue of a diol”means a portion of a diol, as described herein, which excludes the twohydroxyl groups of the diol. The corresponding di-acid or diolcontaining the “residue” thereof is used in synthesis of the co-polymercompositions. The residue of the di-acid or diol is reconstituted invivo (or under similar conditions of pH, aqueous media, and the like) tothe corresponding diol or di-acid upon release from the co-polymercomposition by biodegradation in a controlled manner that depends uponthe properties of the PEA or PEUR co-polymer selected to fabricate thecomposition, which properties are as described herein, for example inthe Examples.

As used herein, the terms “α-amino acid-containing”, and “α-amino acid”mean a chemical compound containing an amino group, a carboxyl group andR₃ or R₄ groups as defined herein. As used herein, the terms “biologicalα-amino acid-containing” and “biological α amino acid” mean the α-aminoacid(s) used in synthesis are naturally occurring L-phenylalanine,leucine, glycine, alanine, valine, isoleucine, lysine, or methionine, ora mixture thereof. Additional biological amino acids used in fabricationof invention co-polymers include lysine and ornithine, but are orientedin the co-polymer backbone adirectionally (i.e., in a non-biologicalorientation) such that the carboxyl group of the amino acid (which maybe substituted by an R⁷ other than H) is pendent rather than beingincorporated into a peptide bond. Additional adirectional amino acidscan be incorporated into the invention compositions by varying the R⁸group as described herein.

As used herein the term “bioactive agent” means an agent, for example asdescribed herein, having a therapeutic, healing or palliative effect inmammals, including humans. A bioactive agent as disclosed herein is notincorporated into the co-polymer backbone, but is dispersed within thePEA or PEUR co-polymer. In one embodiment, at least two differentbioactive agents are dispersed in the invention co-polymer compositions.As used herein, the term “dispersed” as used to refer to bioactiveagents, means the bioactive agents are intermixed, dissolved, orhomogenized with, and/or covalently bound to a PEA or PEUR co-polymer inthe composition. For example, the bioactive agent can be attached, asdescribed herein, to a functional group in the PEA or PEUR co-polymer ofthe composition or to the surface of a co-polymer particle or surgicaldevice made using the invention PEA and PEUR co-polymer compositions.

The term, “biodegradable, biocompatible” as used herein to describe theinvention PEA and PEUR co-polymer compositions means the co-polymer iscapable of being broken down into innocuous products in the normalfunctioning of the body. Biocompatibility is optimized when the aminoacids used in fabrication of the invention co-polymers are biologicalα-amino acids. In addition, biological enzymes facilitate hydrolysis ofester and cleavage of amide linkages in the invention co-polymercompositions to provide biodegradability. The invention co-polymers aretypically chain terminated predominantly with amino groups. Optionally,the amino termini of the co-polymers can be acetylated or otherwisecapped by conjugation to any other acid-containing biocompatiblemolecule, to include without restriction organic acids, bioinactivebiologics, other co-polymers, and bioactive agents as described herein.In one embodiment, the entire co-polymer composition, and any particles,or surgical device made thereof, such as an internal fixation device,are substantially biodegradable.

Accordingly, in one embodiment, the invention provides PEA and PEURco-polymer compositions having a chemical structure described by generalstructural formula (I): wherein m is about 0.01 to about 0.99; p isabout 0.99 to about 0.01; and wherein n is about 5 to about 100; and

wherein R¹ is independently selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and combinations thereof; R³sand R⁴s in a single co-monomer m or p, respectively, are independentlyselected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl and —(CH₂)₂S(CH₃);R⁵ is selected from bicyclic-fragments of 1,4:3,6-dianhydrohexitols ofstructural formula (II); and

R⁶ is selected from the group consisting of (C₂-C₂₀) alkylene, (C₂-C₂₀)alkenylene or alkyloxy;

or a PEA having a chemical structure described by general structuralformula (III):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and q is about 0.99 to 0.01; and wherein n is about 5 to about 100; and

wherein R¹ is independently selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and combinations thereof; R³sand R⁴s in a single co-monomer m or p, respectively, are independentlyselected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl and —(CH₂)₂S(CH₃);R⁵ is selected from bicyclic-fragments of 1,4:3,6-dianhydrohexitols ofstructural formula (II); R⁶ is selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene or alkyloxy; R⁷ is hydrogen,(C₆-C₁₀) aryl (C₁-C₆) alkyl or a protecting group; and R⁸ isindependently (C₁-C₂₀) alkyl or (C₂-C₂₀) alkenyl, for example R⁸ isindependently (C₃ to C₆) alkyl or (C₃ to C₆) alkenyl;

or a PEUR co-polymer having a chemical structure described by generalstructural formula (IV):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and n is about 5 to about 100;

and wherein R² is selected from the group consisting of (C₂-C₂₀)alkylene, (C₂-C₂₀) alkenylene, and bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (III); the R³s and R⁴sin a single co-monomer m or p, respectively, are independently selectedfrom the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl, and —(CH₂)₂S(CH₃); R⁵ isselected from the group consisting of (C₂-C₂₀) alkylene, and (C₂-C₂₀)alkenylene or alkyloxy; R⁶ is selected from bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (II);

or a PEUR having a chemical structure described by general structuralformula (V):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01; qis about 0.99 to 0.01; and n is about 5 to about 100;

and wherein R² is selected from the group consisting of (C₂-C₂₀)alkylene, (C₂-C₂₀) alkenylene, and bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (II); the R³s and R⁴s ina single co-monomer m or p, respectively, are independently selectedfrom the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl, and —(CH₂)₂S(CH₃); R⁵ isselected from the group consisting of (C₂-C₂₀) alkylene, and (C₂-C₂₀)alkenylene or alkyloxy; R⁶ is selected from bicyclic-fragments of1,4:3,6-dianhydrohexitols of structural formula (II); R⁷ is hydrogen,(C₆-C₁₀)aryl (C₁-C₆) alkyl or a protecting group; and R⁸ isindependently (C₁-C₂₀) alkyl or (C₂-C₂₀) alkenyl.

In one embodiment, R⁸ is independently (C₃ to C₆) alkyl or (C₃ to C₆)alkenyl, for example —(CH₂)₄—.

In one alternative, at least one of the α-amino acids used infabrication of the invention co-polymers is a biological α-amino acid.For example, when the R³s or R⁴s are CH₂Ph, the biological α amino acidused in synthesis is L-phenylalanine. In alternatives wherein the R³s orR⁴s are CH₂—CH(CH₃)₂, the co-polymer contains the biological a aminoacid, leucine. By independently varying the R³s and R⁴s withinvariations of the two co-monomers as described herein, other biologicalα-amino acids can also be used, e.g., glycine (when the R³s or R⁴s areH), alanine (when the R³s or R⁴s are CH₃), valine (when the R³s or R⁴sare CH(CH₃)₂), isoleucine (when the R³s or R⁴s are CH(CH₃)—CH₂—CH₃),phenylalanine (when the R³s or R⁴s are CH₂—C₆H₅), lysine (when the R³sor R⁴s=(CH₂)₄—NH₂); or methionine (when the R³s or R⁴s are—(CH₂)₂S(CH₃), and mixtures thereof. In yet another embodiment, all ofthe various α-amino acids contained in the invention PEA and PEURco-polymers are such biological α-amino acids, as described herein.

The term “aryl” is used with reference to structural formulas herein todenote a phenyl radical or an ortho-fused bicyclic carbocyclic radicalhaving about nine to ten ring atoms in which at least one ring isaromatic. In certain embodiments, one or more of the ring atoms can besubstituted with one or more of nitro, cyano, halo, trifluoromethyl, ortrifluoromethoxy. Examples of aryl include, but are not limited to,phenyl, naphthyl, and nitrophenyl.

The term “alkenylene” is used with reference to structural formulasherein to mean a divalent branched or unbranched hydrocarbon chaincontaining at least one unsaturated bond in the main chain or in a sidechain.

In addition, the co-polymer molecules may optionally have a bioactiveagent conjugated thereto via a linker or incorporated into a crosslinkerbetween molecules.

Further, the PEA and PEUR co-polymer compositions suitable for use inthe practice of the invention bear functionalities that allow the optionof covalent attachment of bioactive agent(s) to the co-polymer.

For example, a co-polymer bearing free carboxyl groups can readily reactwith an amino moiety, thereby covalently bonding a peptide to theco-polymer via the resulting amide group. As will be described herein,the biodegradable co-polymer and a bioactive agent may contain numerouscomplementary functional groups that can be used to covalently attachthe bioactive agent to the biodegradable co-polymer.

Further examples of PEA and PEUR co-polymers related to thosecontemplated for use in the practice of the invention and methods ofsynthesis include those set forth in U.S. Pat. Nos. 5,516,881;5,610,241; 6,476,204; and 6,503,538; and in U.S. application Ser. Nos.10/096,435; 10/101,408; 10/143,572; 10/194,965 and 10/362,848.

In certain embodiments, particles or a surgical device made from orcontaining the invention PEA and PEUR co-polymer composition, asdescribed herein, plays an active role in the treatment processes at thesite of implant or use by holding the co-polymer and any bioactiveagents dispersed therein at the site for a period of time sufficient toallow the subject's endogenous processes to slowly release particles orco-polymer molecules from the implanted composition. Meanwhile, thesubject's endogenous processes biodegrade the co-polymer so as torelease bioactive agents dispersed in the co-polymer. Fragile bioactiveagents dispersed in the invention compositions are protected by the moreslowly biodegrading co-polymer to increase half-life and persistence ofthe bioactive agent(s) locally at the site of use, e.g., implant. Adetailed description of methods of making particles using PEA and PEURco-polymers may be found in co-pending U.S. application Ser. No.11/344,689, filed Jan. 31, 2006, which is incorporated herein in itsentirety.

The invention biodegradable co-polymer compositions preferably haveweight average molecular weights ranging from 15,000 to 600,000 Daltons;these copolymers typically have inherent viscosities at 25° C.,determined by standard viscosimetric methods, ranging from 0.3 to 3.5,preferably ranging from 0.4 to 2.0.

The molecular weights and polydispersities herein are determined by gelpermeation chromatography (GPC) using polystyrene standards. Moreparticularly, number and weight average molecular weights (M_(n) andM_(w)) are determined, for example, using a Model 510 gel permeationchromatographer (Water Associates, Inc., Milford, Mass.) equipped with ahigh-pressure liquid chromatographic pump, a Waters 486 UV detector anda Waters 2410 differential refractive index detector. Tetrahydrofuran(THF) or N,N-dimethylacetamide (DMAc) is used as the eluent (1.0 mL/min)The polystyrene standards have a narrow molecular weight distribution.

Methods for making co-polymers containing α-amino acids in thestructural formula are well known in the art and as described herein.For example, for the embodiment of the co-polymer of formula (I), aα-amino acid can be converted into a bis-(α-amino acid) diester monomer,for example, by condensing the α-amino acid with a diol as describedherein. As a result, ester bonds are formed. Then, the bis-(α-aminoacid) diester is entered into a polycondensation reaction with adi-acid, such as sebacic acid, to obtain the final co-polymer havingboth ester and amide bonds. Alternatively, instead of the di-acid, anactivated di-acid derivative, e.g., bis-(p-nitrophenyl) diester, can beused as an activated di-acid, for co-polymers of chemical structure (I)or (III).

Additionally, a bis-carbonate, such as bis-(p-nitrophenyl)dicarbonate,can be used as the activated species to obtain co-polymers of structure(IV or V), in which a final co-polymer is obtained having both ester andurethane bonds.

More particularly, synthesis of the unsaturated poly(ester-amide)s(UPEAs) useful as biodegradable co-polymers of the structure (I) or(III) as described above will be described wherein

for example, and/or (b) R³ or R⁴ is —CH₂—CH═CH—CH₂—. In cases where (a)is present and (b) is not present, R³ or R⁴ is —C₄H₈— or —C₆H₁₂—. Incases where (a) is not present and (b) is present, R¹ or is —C₄H₈— or—C₈H₁₆—.

The UPEAs can be prepared by solution polycondensation of either (1)di-p-toluene sulfonic acid salt of bis (α amino acid) diesters,comprising at least 1 double bond in the diol residue, a di-p-toluenesulfonic acid salt of a bis (α amino acid) diesters, comprising a diolof structural formula (III), and di-p-nitrophenyl esters of saturateddicarboxylic acid or (2) two di-p-toluene sulfonic acid salts ofbis-(α-amino acid) diesters, comprising no double bonds in the diolresidues, and di-nitrophenyl ester of unsaturated dicarboxylic acid or(3) two di-p-toluene sulfonic acid salts of bis-(α-aminoacid)-diol-diesters, comprising at least one double bond in one of thediol residues in the co-polymer general structural formula, the otherdiol residue having structural formula (II), and di-nitrophenyl estersof unsaturated dicarboxylic acids.

Salts of p-toluene sulfonic acid are known for use in synthesizingco-polymers containing amino acid residues. The aryl sulfonic acid saltsare used instead of the free base because the aryl sulfonic salts ofbis-(α-amino acid)-diol-diesters are easily purified throughrecrystallization and render the amino groups as unreactive ammoniumtosylates throughout workup. In the polycondensation reaction, thenucleophilic amino group is readily revealed through the addition of anorganic base, such as triethylamine, so the co-polymer product isobtained in high yield.

For unsaturated co-polymers of structure (I or II), the di-p-nitrophenylesters of unsaturated dicarboxylic acid can be synthesized fromp-nitrophenol and unsaturated dicarboxylic acid chloride, e.g., bydissolving triethylamine and p-nitrophenol in acetone and addingunsaturated dicarboxylic acid chloride dropwise with stiffing at −78° C.and pouring into water to precipitate product. Suitable acid chloridesincluded fumaric, maleic, mesaconic, citraconic, glutaconic, itaconic,ethenyl-butane dioic and 2-propenyl-butanedioic acid chlorides. Forco-polymers of structure (IV or V), bis-(p-nitrophenyl) dicarbonates ofsaturated or unsaturated diols are used as the activated monomer.Dicarbonate monomers of general structure (VI) are employed forco-polymers of structure (IV and V)

wherein each R⁹ is independently (C₆-C₁₀) aryl optionally substitutedwith one or more nitro, cyano, halo, trifluoromethyl, ortrifluoromethoxy; and R⁶ is independently (C₂-C₂₀) alkylene or (C₂-C₂₀)alkyloxy, (C₂-C₂₀) alkenylene or other diol residue having structuralformula (II).

The di-aryl sulfonic acid salts of bis-(α-amino acid) diesters ofsaturated and unsaturated diols can be prepared by admixing α-aminoacid, aryl sulfonic acid (e.g., p-toluene sulfonic acid monohydrate) andsaturated or unsaturated diol in toluene, heating to reflux temperature,until water evolution is minimal, then cooling. The unsaturated diolsinclude, for example, 2-butene-1,4-diol and 1,18-octadec-9-en-diol.

Saturated bis-(p-nitrophenyl) diesters of dicarboxylic acid andsaturated di-p-toluene sulfonic acid salts of bis-(α-amino acid)diesters can be prepared as described in U.S. Pat. No. 6,503,538 B1.

Although the invention bis-(α-amino acid)-containing co-polymercompositions are poly(ester amides) (PEAs) and poly(ester urethanes)(PEURs) made by polycondensation of components as described above, inthe present invention, the components include a di-p-toluenesulfonicacid salt of bis-(α amino acid)-1,4:3,6-dianhydrosorbitol diester; adi-p-toluenesulfonic acid salt of bis-(α amino acid)-aliphatic α,ω-dioldiester and a di-p-nitrophenyl aliphatic (fatty) dicarboxylic acid. Bycontrast, PEUR co-polymers, of structural formula (V) are made bycondensation of at least three components, bis-(α-amino acid) diestersof at least two different types of diols, one of which contains theresidue of a bicyclic-fragment of 1,4:3,6-dianhydrohexitol; and one ofwhich is a di-carbonate of one or more fatty acids.

The bis-(p-nitrophenyl) diesters of dicarboxylic acids are used becausethe p-nitrophenyl ester is a very good leaving group that can promotethe condensation reaction to move to the right of the reaction equationso the co-polymer product is obtained in high yield. In addition, thebis-(p-nitrophenyl) diesters are stable throughout workup and can behandled and dried in open atmosphere.

The di-aryl sulfonic acid salts of bis-(α-amino acid) diesters ofunsaturated diols can be prepared by admixing α-amino acid, p-arylsulfonic acid (e.g. p-toluene sulfonic acid monohydrate) and saturatedor unsaturated diol in toluene, heating to reflux temperature, untilwater evolution is minimal, then cooling. The unsaturated diols include,for example, 2-butene-1,4-diol and 1,18-octadec-9-en-diol.

A working example of a diamine monomer having structural formula (III),in U.S. Pat. No. 6,503,538 is provided by substituting p-toluenesulfonic acid salt of bis-(L-phenylalanine)-2-butene-1,4-diester for(III) in Example 1 of U.S. Pat. No. 6,503,538 or by substitutingbis-(p-nitrophenyl) fumarate for (V) in Example 1 of U.S. Pat. No.6,503,538 or by substituting p-toluene sulfonic acid salt ofbis-(L-phenylalanine) 2-butene-1,4-diester for III in Example 1 of U.S.Pat. No. 6,503,538 and also substituting bis-(p-nitrophenyl) fumaratefor (V) in Example 1 of U.S. Pat. No. 6,503,538.

In unsaturated PEA or PEUR, the following hold: Aminoxyl radical e.g.,4-amino TEMPO can be attached using carbonyldiimidazol, or suitablecarbodiimide, as a condensing agent. Optionally, bioactive agents, asdescribed herein, can be attached via a double bond functionality,preferably one that does not occur in a residue of a bioactive agent inthe co-polymer backbone. Hydrophilicity, if desired, can be imparted bybonding to poly(ethylene glycol) diacrylate.

The description and methods of synthesis of structurally related PEA andPEUR co-polymers are set forth in U.S. Pat. Nos. 5,516,881; 6,476,204;6,503,538, the entire content of each of which is incorporated herein byreference.

The PEA and PEUR co-polymers described herein have weight averagemolecular weights ranging from 15,000 to 600,000 Daltons; theseco-polymers typically have inherent viscosities at 25° C., determined bystandard viscosimetric methods, ranging from 0.3 to 4.0, preferablyranging from 0.4 to 2.0.

The PEA and PEUR co-polymers described herein can be fabricated in avariety of molecular weights and a variety of relative proportions ofthe two bis-(α amino acid)-containing units and optional Lysine-basedmonomer of the co-polymer. The appropriate molecular weight for aparticular use is readily determined by one of skill in the art based onthe guidelines contained herein and the mechanical properties disclosed.Thus, e.g., a suitable molecular weight will be on the order of about15,000 to about 600,000 Daltons, for example about 15,000 to about400,000, or about 15,000 to about 300,000.

The invention biodegradable, biocompatible PEA and PEUR copolymersuseful in the co-polymer particles, compositions, and biodegradablesurgical devices biodegrade by enzymatic action at the surface.Therefore, the co-polymers, for example particles thereof, facilitate invivo release of a bioactive agent dispersed in the co-polymer at acontrolled release rate, which is specific and constant over a prolongedperiod. Additionally, since PEA and PEUR co-polymers break down in vivovia enzymes without production of adverse side products, the co-polymersin the invention compositions and surgical devices, such as those thatproduce biological α-amino acids upon break down, are substantiallynon-inflammatory.

Synthesis of the unsaturated poly(ester-amide)s (UPEAs) useful asbiodegradable co-polymers of the structure (I) as described above willnow be described. Compounds having the structure (II) can be made insimilar fashion to the compound (VII) of U.S. Pat. No. 6,503,538 B1,except that R⁴ of (III) of U.S. Pat. No. 6,503,538 and/or R¹ of (V) ofU.S. Pat. No. 6,503,538 is (C₂-C₂₀) alkenylene as described above.Unsaturated copolymers, co-UPEAs containing different feed ratios of twodiamine monomers R⁴ of (III) of U.S. Pat. No. 6,503,538 will havecombinations of above described (C₂-C₂₀) alkenylene and residue of1,4:3,6-dianhydrohexitols. And/or R¹ in (V) of U.S. Pat. No. 6,508,538is (C₂-C₂₀) alkenlylene, or combinations of alkenylene and fatty acidresidues with various feed ratios. Reaction is carried out, for example,by adding dry triethylamine to a mixture of said (III) and (IV) of U.S.Pat. No. 6,503,538 and said (V) of U.S. Pat. No. 6,503,538 in dryN,N-dimethylacetamide, at room temperature, then increasing thetemperature to 80° C. and stirring for 16 hours. The reaction solutionis then cooled to room temperature, diluted with ethanol, poured intowater, co-polymer is separated and washed with water, dried to about 30°C. under reduced pressure and then purified up to negative test onp-nitrophenyl and p-toluene sulfonic acid. A preferred reactant (IV) ofU.S. Pat. No. 6,503,538 is p-toluene sulfonic acid salt of lysine benzylester, the benzyl ester protecting group is preferably removed from (I)to confer biodegradability, but it should not be removed byhydrogenolysis as in Example 22 of U.S. Pat. No. 6,503,538 becausehydrogenolysis would saturate the desired double bonds; rather thebenzyl ester group should be converted to an acid group by a method thatwould preserve unsaturation, e.g., by treatment with fluoroacetic acidor gaseous HF. Alternatively, the lysine reactant (IV) of U.S. Pat. No.6,503,538 can be protected by a protecting group different from benzylwhich can be readily removed in the finished product while preservingunsaturation, e.g., the lysine reactant can be protected with t-butyl(i.e., the reactant can be t-butyl ester of lysine) and the t-butyl canbe converted to the “H” form (free carboxylic acid) while preservingunsaturation by treatment of the product (II) with acid.

In unsaturated compounds having structural formula (I) or (III), thefollowing hold: An amino substituted aminoxyl (N-oxide) radical bearinggroup e.g., 4-amino TEMPO, can be attached using carbonyldiimidazole, orsuitable carbodiimide, as a condensing agent. Bioactive agents, and thelike, as described herein, optionally can be attached via the doublebond functionality. Hydrophilicity can be imparted by bonding topoly(ethylene glycol) diacrylate.

The PEA and PEUR co-polymers and blends thereof contemplated for use inthe practice of the invention can be synthesized by a variety of methodswell known in the art. For example, tributyltin (IV) catalysts arecommonly used to form polyesters such as poly(caprolactone),poly(glycolide), poly(lactide), and the like. However, it is understoodthat a wide variety of catalysts can be used to form co-polymerssuitable for use in the practice of the invention.

Such poly(caprolactones) contemplated for use as above have an exemplarystructural formula (VII) as follows:

Poly(glycolides) contemplated for use have an exemplary structuralformula (VIII) as follows:

Poly(lactides) contemplated for use have an exemplary structural formula(IX) as follows:

An exemplary synthesis of a suitable poly(lactide-co-ε-caprolactone)including an aminoxyl moiety is set forth as follows. The first stepinvolves the copolymerization of lactide and ε-caprolactone in thepresence of benzyl alcohol using stannous octoate as the catalyst toform a co-polymer of structural formula (X).

The hydroxy terminated co-polymer chains can then be capped with maleicanhydride to form co-polymer chains having structural formula (XI):

At this point, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxy can bereacted with the carboxylic end group to covalently attach the aminoxylmoiety to the copolymer via the amide bond that results from thereaction between the 4-amino group and the carboxylic acid end group.Alternatively, the maleic acid capped copolymer can be grafted withpolyacrylic acid to provide additional carboxylic acid moieties forsubsequent attachment of further aminoxyl groups.

Due to the versatility of the PEA and PEUR co-polymers used in theinvention compositions, the relative amounts of stiffness and elongationproperties of the co-polymers as well as the biodegradation rates can becontrolled by varying the proportions of the two bis-(α-aminoacid)-containing monomers, the adirectional amino acid-based monomer andother building blocks of the co-polymer. For example, Table 1 belowillustrates the differences in Tg, tensile stress at yield, percentelongation and Young's modulus of PEA co-polymers of structural formula(I) and how relative proportions of the two bis-(α aminoacid)-containing monomers in the invention co-polymers affect thevarious properties. For example, Table 1 below illustrates theproperties of copolyesteramides (co-PEAs) composed of adipic acid andvarious feed ratios of two diamine-diester monomers:bis-(L-leucine)-1,6-hexanediol-diester (Leu(6)) andbis-(L-leucine)-1,4:3,6-dihianhydrosorbitol (Leu(DAS)).

TABLE 1 Tensile Stress Percent Young's Tg^(a)) at Yield ElongationModulus Polymer designation (° C.) (Mpa) (%) (Mpa) 4-Leu(DAS) 105.0 Nofilm formation 4-Leu(DAS)75%-Leu(6)25% 90.7 56 5 22994-Leu(DAS)45%-Leu(6)55% 69.0 39 82 1431 4-Leu(DAS)20%-Leu(6)80% 53.4 28339 1067 ^(a))Tg was taken from second heating curve with heating rateof 10 C./min by DSC measurement.

Further, as shown in the Examples, addition to any given co-polymer offormulas (I) and (IV) of a third L-lysine-based unit as in structuralformulas (II) and (V) (as shown in Table 2 below) will provide anadditional measure of percent elongation (%) (“strechability”) to theco-polymer, and will vary depending on the nature of the substituent onthe C-terminus of L-lysine. In general, the invention PEA and PEURco-polymers formed as described herein, for example, in the Examplesherein, can be expected to have the following mechanical properties.

-   -   1. A glass transition temperature in the range from about 22° C.        to about 120° C., for example, in the range from about 37° C. to        about 80° C.;    -   2. A film of the co-polymer with an average thickness of about        0.125 mm has a tensile stress at yield of about 25 Mpa to about        90 Mpa, for example, about 30 Mpa to about 60 Mpa;    -   3. A film of the co-polymer with an average thickness of about        0.125 mm has a percent elongation of about 2% to about 400%, for        example about 65% to about 300%; and    -   4. A film of the co-polymer with an average thickness of about        0.125 mm has a Young's modulus in the range from about 400 Mpa        to about 3000 Mpa, for example about 1000 Mpa to about 2500 Mpa.        Thus, by judicious choice of the content and relative        proportions of the three building block units, one skilled in        the art can obtain an invention bis-(α-amino acid)-containing        PEA or PEUR co-polymer that is both biodegradable and        biocompatible and which possesses a wide range of mechanical        properties.

The designations used to label the PEAs and PEURs in Tables 1 and 2 andin the Examples herein are according to the following formula for eachof the primary and secondary bis-(α-amino acid)-containing units of theco-polymer: y-(*)AA₁-x₁-%-(*)AA₂-x₂-% wherein y is the number ofmethylene groups in the dicarboxylic acid residue, (*) indicates theorientation of the following amino acid, x₁ indicates the type ofbicyclic-fragment of 1,4:36-dianyhydrohexitol bis-(α-aminoacid)-containing unit in one of the bis-(α-amino acid)-containing unitsand x₂ indicates the number of methylene groups in the diol residue ofthe other bis-(α-amino acid)-containing unit, AA₁ and AA₂ indicate theα-amino acids in the two bis-(α-amino acid)-containing units. AA₁ andAA₂ may be identical or different. For example, AA=Phe for phenylalanine(R³ and/or R⁴═CH₂Ph) and Leu for leucine (R³ and/or R⁴═CH₂CH(CH₃)₂);where y=4 means adipic acid, or y=Fum designates unsaturated fumaricacid. Where x=DAS designates a 1,4:3,6-dianhydrosorbitol. In a similarmanner the co-PEA 4-[L-Leu-DAS]_(0.75)-[L-Leu-6]_(0.25) (Compound #2,Table 1) means: random co-poly(ester amide), based on adipic acid (y=4)containing 75 mol % of bis-(L-leucine)-1,4:3,6 dianhydrosorbitol-diesterand 25% bis-(L-leucine)-1,6-hexanediol-diester.

In certain embodiments, a bioactive agent can be dispersed into theco-polymer by intermixing into the co-polymer solution or by “loading”onto the co-polymer without formation of a chemical bond. Alternatively,a bioactive agent can be linked to any free functional group in theco-polymers, such as an amino, hydroxyl (alcohol), thiol, and the like,to form a direct linkage. Such a linkage can be formed from suitablyfunctionalized starting materials using synthetic procedures that areknown in the art.

In certain embodiments, a bioactive agent can be covalently bound to thebiodegradable co-polymers via a wide variety of suitable functionalgroups. For example, when the biodegradable co-polymer is a polyester,the carboxyl group chain end can be used to react with a complimentarymoiety on the bioactive agent, such as hydroxy, amino, thio, and thelike. A wide variety of suitable reagents and reaction conditions aredisclosed, e.g., in March's Advanced Organic Chemistry, Reactions,Mechanisms, and Structure, Fifth Edition, (2001); and ComprehensiveOrganic Transformations, Second Edition, Larock (1999).

For example, a co-polymer of the present invention can be linked to thebioactive agent via a carboxyl group (e.g., COOH) of the co-polymer.Specifically, a compound of structures (I and III-VI) can react with anamino functional group of a bioactive agent or a hydroxyl functionalgroup of a bioactive agent to provide a biodegradable, biocompatibleco-polymer having the bioactive agent attached via an amide linkage orester linkage, respectively. In another embodiment, the carboxyl groupof the co-polymer of structure (III or VI) wherein R⁷═H can betransformed into an acyl halide, acyl anhydride/“mixed” anhydride, oractive ester.

Alternatively still, the bioactive agent may be attached to theco-polymer via a linker. Indeed, to improve surface hydrophobicity ofthe biodegradable co-polymer, to improve accessibility of thebiodegradable co-polymer towards enzyme activation, and to improve therelease profile of the biodegradable co-polymer, a linker may beutilized to indirectly attach the bioactive agent to the biodegradableco-polymer. In certain embodiments, the linker compounds includepoly(ethylene glycol) having a molecular weight (Mw) of about 44 toabout 10,000, preferably 44 to 2000; amino acids, such as serine;polypeptides with repeat units from 1 to 100; and any other suitable lowmolecular weight co-polymers. The linker typically separates thebioactive agent from the co-polymer by about 5 angstroms up to about 200angstroms.

In still further embodiments, the linker is a divalent radical offormula W-A-Q, wherein A is (C₁-C₂₄) alkyl, (C₂-C₂₄) alkenyl, (C₂-C₂₄)alkynyl, (C₂-C₂₀) alkyloxy, (C₃-C₈) cycloalkyl, or (C₆-C₁₀) aryl, and Wand Q are each independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—,—C(═O)O, —O—, —S—, —S(O), —S(O)₂—, —S—S—, —N(R)—, —C(═O)—, wherein eachR is independently H or (C₁-C₆) alkyl.

As used herein, the term “alkyl”, as applied to the linkers describedherein, refers to a straight or branched chain hydrocarbon groupincluding methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-hexyl, and the like.

As used herein, “alkenyl”, as applied to the linkers described herein,refers to straight or branched chain hydrocarbon groups having one ormore carbon-carbon double bonds.

As used herein, “alkynyl”, as applied to the linkers described herein,refers to straight or branched chain hydrocarbon groups having at leastone carbon-carbon triple bond.

As used herein, “aryl”, as applied to the linkers described herein,refers to aromatic groups having in the range of 6 up to 14 carbonatoms.

In certain embodiments, the linker may be a polypeptide having fromabout 2 up to about 25 amino acids. Suitable peptides contemplated foruse include poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-threonine, poly-L-tyrosine,poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-arginine,poly-L-lysine-L-tyrosine, and the like.

The linker can be attached first to the co-polymer or to the bioactiveagent. During synthesis of co-polymers having bioactive agentsindirectly attached via a linker, the linker can be either inunprotected form or protected from, using a variety of protecting groupswell known to those skilled in the art.

In the case of a protected linker, the unprotected end of the linker canfirst be attached to the co-polymer or the bioactive agent. Theprotecting group can then be de-protected using Pd/H₂ hydrogenolysis forsaturated co-polymers, mild acid or base hydrolysis for unsaturatedco-polymers, or any other common de-protection method that is known inthe art. The de-protected linker can then be attached to the bioactiveagent. An example using poly(ethylene glycol) as the linker is shown inScheme 1.

-   Scheme 1: Poly(ethylene glycol) employed as the linker between    co-polymer and bioactive agent.

-   wherein    represents the co-polymer;-   R can be a bioactive agent; and-   n can range from 1 to 200; preferable from 1 to 50.

An exemplary conjugate synthesis performed on a biodegradable co-polymeraccording to the invention (wherein the molecule to be attached to theco-polymer is an amino substituted aminoxyl N-oxide radical) is setforth as follows. A biodegradable co-polymer herein can be reacted withan aminoxyl radical containing compound, e.g.,4-amino-2,2,6,6-tetramethylpiperidine-1-oxy, in the presence ofN,N′-carbonyl diimidazole or suitable carbodiimide, to replace thehydroxyl moiety in the carboxyl group, either on the pendant carboxylicacids of the PEAs, PEURs or UPEAs, or at the chain end of a polyester asdescribed, with an amide linkage to the aminoxyl (N-oxide) radicalcontaining group. The amino moiety covalently bonds to the carbon of thecarbonyl residue such that an amide bond is formed. TheN,N′-carbonyldiimidazole or suitable carbodiimide converts the hydroxylmoiety in the carboxyl group at the chain end of the polyester into anintermediate activated moiety which will react with the amino group ofthe aminoxyl (N oxide) radical compound, e.g., the amine at position 4of 4-amino-2,2,6,6-tetramethylpiperidine-1-oxy. The aminoxyl reactant istypically used in a mole ratio of reactant to polyester ranging from 1:1to 100:1. The mole ratio of N,N′-carbonyldiimidazole or carbodiimide toaminoxyl is preferably about 1:1.

A typical reaction is as follows. A polyester is dissolved in a reactionsolvent and reaction is readily carried out at the temperature utilizedfor the dissolving. The reaction solvent may be any in which thepolyester will dissolve; this information is normally available from themanufacturer of the polyester. When the polyester is a polyglycolic acidor a poly(glycolide-L-lactide) (having a monomer mole ratio of glycolicacid to L-lactic acid greater than 50:50), highly refined (99.9+% pure)dimethyl sulfoxide at 115° C. to 130° C. or DMSO at room temperaturesuitably dissolves the polyester. When the polyester is a poly-L-lacticacid, a poly-DL-lactic acid or a poly(glycolide-L-lactide) (having amonomer mole ratio of glycolic acid to L-lactic acid 50:50 or less than50:50), tetrahydrofuran, dichloromethane (DCM) and chloroform at roomtemperature to 40˜50° C. suitably dissolve the polyester.

The product may be precipitated from the reaction mixture by adding coldnon-solvent for the product. For example, aminoxyl-containingpolyglycolic acid and aminoxyl-containing poly(glycolide-L-lactide)formed from glycolic acid-rich monomer mixture are readily precipitatedfrom hot dimethylsulfoxide by adding cold methanol or coldacetone/methanol mixture and then recovered, e.g., by filtering. Whenthe product is not readily precipitated by adding cold non-solvent forthe product, the product and solvent may be separated by using vacuumtechniques. For example, aminoxyl-containing poly-L-lactic acid isadvantageously separated from solvent in this way. The recovered productis readily further purified by washing away water and by-products (e.g.urea) with a solvent which does not dissolve the product, e.g., methanolin the case of the modified polyglycolic acid, polylactic acid andpoly(glycolide-L-lactide) products herein. Residual solvent from suchwashing may be removed using vacuum drying.

The invention PEA and PEUR co-polymer compositions can be formulatedinto particles to provide a variety of properties. The particles canhave a variety of sizes and structures suitable to meet differingtherapeutic goals and routes of administration using methods describedin full in co-pending U.S. application Ser. No. 11/344,689, filed Jan.31, 2006.

Water soluble covering molecule(s), such as poly(ethylene glycol) (PEG);phosphatidylcholine (PC); glycosaminoglycans including heparin;polysaccharides including chitosan, alginates and polysialic acid;poly(ionizable or polar amino acids) including polyserine, polyglutamicacid, polyaspartic acid, polylysine and polyarginine; as describedherein, and targeting molecules, such as antibodies, antigens andligands, are bioactive agents that can also be conjugated to theco-polymer on the exterior of particles or surgical devices formed fromthe invention co-polymer compositions after production. Such covering ortargeting molecules may be used, respectively, to block active sites onthe particles or surgical devices not occupied by a bioactive agent orto target delivery of the particles to a specific body site as is knownin the art. The molecular weights of PEG molecules on a single particlecan be substantially any molecular weight in the range from about 200 toabout 200,000, so that the molecular weights of the various PEGmolecules attached to the particle can be varied.

Alternatively, a bioactive agent or covering molecule can be attached tothe co-polymer particles or surgical devices made using the inventionPEA and PEUR co-polymers via a linker molecule, as described herein. Thelinker can be attached first to the co-polymer or to the bioactive agentor covering molecule. During synthesis, the linker can be either inunprotected form or protected from, using a variety of protecting groupswell known to those skilled in the art. In the case of a protectedlinker, the unprotected end of the linker can first be attached to theco-polymer particle or surgical device or to the bioactive agent orcovering molecule. The protecting group can then be de-protected usingPd/H₂ hydrogenation for saturated co-polymer backbones, mild acid orbase hydrolysis for unsaturated co-polymers, or any other commonde-protection method that is known in the art. The de-protected linkercan then be attached to the bioactive agent or covering molecule, or tothe co-polymer in the particles or surgical devices.

In an alternative embodiment, a bioactive agent can covalently crosslinkmolecules of the co-polymer, i.e. the bioactive agent is bound to morethan one co-polymer molecule, to form an intermolecular bridge. Thiscovalent crosslinking can be done with or without a linker containingthe bioactive agent.

A bioactive agent molecule can also be incorporated into anintramolecular bridge by covalent attachment between two sites on thesame co-polymer molecule.

A linear co-polymer/polypeptide conjugate is made by protecting thepotential nucleophiles on the polypeptide backbone and leaving only onereactive group to be bound to the co-polymer or co-polymer/linkerconstruct. Deprotection is performed according to methods well known inthe art for deprotection of peptides (Boc and Fmoc chemistry forexample).

In one embodiment of the present invention, a bioactive agent is apolypeptide presented as a retro-inverso or partial retro-inversopeptide.

In another embodiment, a bioactive agent may be intermixed with (e.g.,matrixed with) a photocrosslinkable version of the co-polymer, such asan unsaturated PEA co-polymer and subjected to photo-initiated radicalcrosslinking. After crosslinking, the co-polymer composition can bedispersed (i.e., ground) to form particles having an average diameter inthe range from about 0.1 to about 10 μm.

Polymer—Bioactive Agent Linkage

In one embodiment, PEA and PEUR co-polymer compositions as describedherein have one or more bioactive agent directly linked to theco-polymer. The residues of the co-polymer can be linked to the residuesof the one or more bioactive agents. For example, one residue of theco-polymer can be directly linked to one residue of a bioactive agent.The co-polymer and the bioactive agent can each have one open valence.Alternatively, more than one bioactive agent, multiple bioactive agents,or a mixture of bioactive agents having different therapeutic orpalliative activity, can be directly linked to the co-polymer. However,since the residue of each bioactive agent can be linked to acorresponding residue of the co-polymer, the number of residues of theone or more bioactive agents corresponds to the number of open valenceson the residue of the co-polymer.

As used herein, a “residue of a co-polymer” refers to a radical of a PEAor PEUR co-polymer described by formulas (I and III-V) having one ormore open valences. Any synthetically feasible atom, atoms, orfunctional group of the co-polymer (e.g., on the co-polymer backbone orpendant group thereof) is substantially retained when the radical isattached to a residue of a bioactive agent. Additionally, anysynthetically feasible functional group (e.g., carboxyl) can be createdon the co-polymer (e.g., on the co-polymer backbone, as a pendant group,or as chain termini) to provide the open valence. Based on the linkagethat is desired, those skilled in the art can select suitablyfunctionalized starting materials that can be used to derivatize the PEAand PEUR co-polymers used in the present invention using procedures thatare known in the art.

For example, the residue of a bioactive agent can be linked to theresidue of a compound of structural formula (I, II, IV and V) through anamide (e.g., —N(R)C(═O)— or C(═O)N(R)—), ester (e.g., —OC(═O)— or—C(═O)O—), ether (e.g., —O—), amino (e.g., —N(R)—), ketone (e.g.,—C(═O)—), thioether (e.g., —S—), sulfinyl (e.g., —S(O)—), sulfonyl(e.g., —S(O)₂—), disulfide (e.g., —S—S—), or a direct (e.g., C—C bond)linkage, wherein each R is independently H or (C₁-C₆) alkyl. Such alinkage can be formed from suitably functionalized starting materialsusing synthetic procedures that are known in the art. Based on thelinkage that is desired, those skilled in the art can select suitablyfunctional starting material to derivatize any residue of a compound ofstructural formula (I, II, IV and V) and thereby conjugate a givenresidue of a bioactive agent using procedures that are known in the art.The residue of the optional bioactive agent can be linked to anysynthetically feasible position on the residue of a compound ofstructural formula (I, II, IV and V). Additionally, the invention alsoprovides compounds having more than one residue of a bioactive agentdirectly linked to a compound of structural formula (I, II, IV and V).

The number of bioactive agents that can be linked to the co-polymermolecule can typically depend upon the molecular weight of theco-polymer. For example, for a compound of structural formula (I) or(IV), wherein n is about 5 to about 150, preferably about 5 to about 70,up to about 300 bioactive agent molecules (i.e., residues thereof) canbe directly linked to the co-polymer (i.e., residue thereof) by reactingthe bioactive agent with terminal groups of the co-polymer. On the otherhand, for a compound of structural formula (II) or (V) up to anadditional 150 bioactive agents can be linked to the co-polymer byreacting the bioactive agent with the pendant group on theLysine-containing unit. In unsaturated co-polymers, additional bioactiveagents can also be reacted with double (or triple) bonds in theco-polymer.

Accordingly, invention co-polymer compositions, either in the form ofparticles or surgical devices, or not, can be covalently attacheddirectly to the bioactive agent, rather than being dispersed or “loaded”into the co-polymer without chemical attachment, using any of severalmethods well known in the art and as described hereinabove. The amountof bioactive agent is generally approximately 0.1% to about 60% (w/w)bioactive agent to co-polymer composition, more preferably about 1% toabout 25% (w/w) bioactive agent, and even more preferably about 2% toabout 20% (w/w) bioactive agent. The percentage of bioactive agent willdepend on the desired dose and the condition being treated, as discussedin more detail below.

In addition to serving as a stand-alone delivery system for bioactiveagents when directly administered in vivo in the form of implantableparticles, the invention PEA and PEUR co-polymer compositions can beused in the fabrication of various types of surgical devices. In thisembodiment, the composition from which the surgical device is fabricatedis effective for controlled delivery to surrounding tissue of one ormore bioactive agents dispersed in the co-polymer in the inventionco-polymer composition, for example, covalently attached to the surfacethereof.

In one embodiment, the invention PEA or PEUR co-polymer composition hassufficient stiffness to be fabricated in the form of a biodegradable,biocompatible surgical device, including but not limited to internalfixation devices, such as surgical suture, surgical screws, implantableplates, and implantable rods, or as vascular stents and dialysis shunts.Any method known in the art for fabrication of biodegradable co-polymersurgical devices, such as extrusion, injection molding, casting, orsolution processing (dry and wet spinning), and the like, can be usedfor this purpose. Such biodegradable, biocompatible surgical devicesslowly biodegrade to create substantially biocompatible breakdownproducts during biodegradation of the invention device, for example overa period of from about two days to a few years, for example three years,four years or six years, depending on the combination of building blocksselected for the PEA or PEUR co-polymer as well depending on suchfactors as device shape, thickness, and mode of fabrication.

Accordingly, in another embodiment the invention provides methods fordelivering a bioactive agent to a subject comprising implanting at aninterior body site an invention surgical device made using an inventionPEA or PEUR copolymer, as described herein, so that the device slowlybiodegrades, for example completely. A bioactive agent dispersed in theco-polymer used to fabricate the device slowly released to tissuesurrounding a site of implantation during biodegradation of the device,for example to promote healing and alleviate pain therein. Inembodiments wherein the PEA or PEUR co-polymer used in fabrication ofthe surgical device is designed to accomplish total biodegradation, noadditional surgery is required to remove the implanted surgical devicedue to its biodegradation properties.

In another embodiment, the invention PEA or PEUR co-polymer compositioncan be fabricated in the form of a biodegradable, biocompatible pad,sheet or wrap of any desired surface area. For example, the co-polymercan be woven or formed as a thin sheet of randomly oriented fibers byelectrospinning to produce nanofibers of the co-polymer. Such pads,sheets and wraps can be used in a number of types of wound dressings fortreatment of a variety of conditions, for example by promotingendogenous healing processes at a wound site. The co-polymer compositionbiodegrades over time, releasing a dispersed bioactive agent to beabsorbed into a wound site where it acts intracellularly, either withinthe cytosol, the nucleus, or both of a target cell, or the bioactiveagent can bind to a cell surface receptor molecule to elicit a cellularresponse without entering the cell. Alternatively, the bioactive agentreleased from the surgical device, for example when fabricated as avascular stent, promotes endogenous healing processes at the wound siteby contact with the surroundings into which the surgical device isimplanted. A detailed description of wound dressings, wound healingimplants and surgical device coatings made using PEA and PEURco-polymers is found in co-pending U.S. patent application Ser. No.11/128,903, filed May 12, 2005.

Bioactive Agents

Bioactive agents contemplated for dispersion within the co-polymers usedin the invention PEA and PEUR co-polymer compositions includeanti-proliferants, rapamycin and any of its analogs or derivatives,paclitaxel or any of its taxene analogs or derivatives, everolimus,sirolimus, tacrolimus, or any of its-limus named family of drugs, andstatins such as simvastatin, atorvastatin, fluvastatin, pravastatin,lovastatin, rosuvastatin, geldanamycins, such as 17AAG(17-allylamino-17-demethoxygeldanamycin); Epothilone D and otherepothilones, 17-dimethylaminoethylamino-17-demethoxy-geldanamycin andother polyketide inhibitors of heat shock protein 90 (Hsp90),cilostazol, and the like.

Suitable bioactive agents for dispersion in the invention PEA and PEURco-polymer compositions and particles made therefrom, also can beselected from those that promote endogenous production of a therapeuticnatural wound healing agent, such as nitric oxide, which is endogenouslyproduced by endothelial cells. Alternatively the bioactive agentsreleased from the co-polymers during degradation may be directly activein promoting natural wound healing processes by endothelial cells. Thesebioactive agents can be any agent that donates, transfers, or releasesnitric oxide, elevates endogenous levels of nitric oxide, stimulatesendogenous synthesis of nitric oxide, or serves as a substrate fornitric oxide synthase or that inhibits proliferation of smooth musclecells. Such agents include, for example, aminoxyls, furoxans,nitrosothiols, nitrates and anthocyanins; nucleosides such as adenosineand nucleotides such as adenosine diphosphate (ADP) and adenosinetriphosphate (ATP); neurotransmitter/neuromodulators such asacetylcholine and 5-hydroxytryptamine (serotonin/5-HT); histamine andcatecholamines such as adrenalin and noradrenalin; lipid molecules suchas sphingosine-1-phosphate and lysophosphatidic acid; amino acids suchas arginine and lysine; peptides such as the bradykinins, substance Pand calcium gene-related peptide (CGRP), and proteins such as insulin,vascular endothelial growth factor (VEGF), and thrombin.

A variety of bioactive agents, coating molecules and ligands forbioactive agents can be attached, for example covalently, to the surfaceof co-polymer particles or surgical devices made using the invention PEAand PEUR co-polymers. Bioactive agents, such as targeting antibodies,polypeptides (e.g., antigens) and drugs can be covalently conjugated toinvention co-polymers at the surface of the co-polymer particles orsurgical devices. For example, small proteinaceous motifs, such as the Bdomain of bacterial Protein A and the functionally equivalent region ofProtein G are known to bind to, and thereby capture, antibody moleculesby the Fc region. Such proteinaceous motifs can be attached as bioactiveagents to the invention co-polymers and compositions, especially to thesurface of the co-polymer particles described herein. Such moleculeswill act, for example, as ligands to attach antibodies for use astargeting ligands or to capture antibodies to hold precursor cells orcapture cells out of the blood stream. Therefore, the antibody typesthat can be attached to co-polymer coatings using a Protein A or ProteinG functional region are those that contain an Fc region. The captureantibodies will in turn bind to and hold precursor cells, such asprogenitor cells, near the co-polymer surface while the precursor cells,which are preferably bathed in a growth medium within the co-polymer,secrete various factors and interact with other cells of the subject. Inaddition, one or more bioactive agents dispersed in the co-polymerparticles, such as the bradykinins, may activate the precursor cells.

In addition, bioactive agents for attaching precursor cells or forcapturing progenitor endothelial cells (PECs) from a blood stream in asubject to which the co-polymer compositions are administered aremonoclonal antibodies directed against a known precursor cell surfacemarker. For example, complementary determinants (CDs) that have beenreported to decorate the surface of endothelial cells include CD31,CD34, CD102, CD105, CD106, CD109, CDw130, CD141, CD142, CD143, CD144,CDw145, CD146, CD147, and CD166. These cell surface markers can be ofvarying specificity and the degree of specificity for a particularcell/developmental type/stage is in many cases not fully characterized.In addition, these cell marker molecules against which antibodies havebeen raised will overlap (in terms of antibody recognition) especiallywith CDs on cells of the same lineage: monocytes in the case ofendothelial cells. Circulating endothelial progenitor cells are some wayalong the developmental pathway from (bone marrow) monocytes to matureendothelial cells. CDs 106, 142 and 144 have been reported to markmature endothelial cells with some specificity. CD34 is presently knownto be specific for progenitor endothelial cells and therefore iscurrently preferred for capturing progenitor endothelial cells out ofblood in the site into which the co-polymer particles are implanted forlocal delivery of the active agents. Examples of such antibodies includesingle-chain antibodies, chimeric antibodies, monoclonal antibodies,polyclonal antibodies, antibody fragments, Fab fragments, IgA, IgG, IgM,IgD, IgE and humanized antibodies, and active fragments thereof.

The following bioactive agents and small molecule drugs will beparticularly effective for dispersion within the invention PEA and PEURco-polymer compositions when selected for their suitable therapeutic orpalliative effect with reference to a wound or disease of interest, orsymptoms thereof, or in experiments designed for in vitro testing ofsuch effects in cells or tissue culture, or in vivo.

In one embodiment, the suitable bioactive agents are not limited to, butinclude, various classes of compounds that facilitate or contribute towound healing when presented in a time-release fashion. Such bioactiveagents include wound-healing cells, including certain precursor cells,which can be protected and delivered by the biodegradable co-polymer inthe invention compositions. Such wound healing cells include, forexample, pericytes and endothelial cells, as well as inflammatoryhealing cells. To recruit such cells to the site of a co-polymer depotin vivo, the invention PEA and PEUR co-polymer compositions andparticles thereof used in the invention and methods of use can includeligands for such cells, such as antibodies and smaller molecule ligands,that specifically bind to “cellular adhesion molecules” (CAMs).Exemplary ligands for wound healing cells include those thatspecifically bind to Intercellular adhesion molecules (ICAMs), such asICAM-1 (CD54 antigen); ICAM-2 (CD102 antigen); ICAM-3 (CD50 antigen);ICAM-4 (CD242 antigen); and ICAM-5; Vascular cell adhesion molecules(VCAMs), such as VCAM-1 (CD106 antigen); Neural cell adhesion molecules(NCAMs), such as NCAM-1 (CD56 antigen); or NCAM-2; Platelet endothelialcell adhesion molecules PECAMs, such as PECAM-1 (CD31 antigen);Leukocyte-endothelial cell adhesion molecules (ELAMs), such as LECAM-1;or LECAM-2 (CD62E antigen), and the like.

In another aspect, the suitable bioactive agents include extra cellularmatrix proteins, macromolecules that can be dispersed into theco-polymer particles used in the invention PEA and PEUR co-polymercompositions, e.g., attached either covalently or non-covalently.Examples of useful extra-cellular matrix proteins include, for example,glycosaminoglycans, usually linked to proteins (proteoglycans), andfibrous proteins (e.g., collagen; elastin; fibronectins and laminin).Bio-mimics of extra-cellular proteins can also be used. These areusually non-human, but biocompatible, glycoproteins, such as alginatesand chitin derivatives. Wound healing peptides that are specificfragments of such extra-cellular matrix proteins and/or their bio-mimicscan also be used.

Proteinaceous growth factors are another category of bioactive agentssuitable for dispersion in the invention PEA and PEUR co-polymercompositions and methods of use described herein. Such bioactive agentsare effective in promoting wound healing and other disease states as isknown in the art, for example, Platelet Derived Growth Factor-BB(PDGF-BB), Tumor Necrosis Factor-alpha (TNF-alpha), Epidermal GrowthFactor (EGF), Keratinocyte Growth Factor (KGF), Thymosin B4; and,various angiogenic factors such as vascular Endothelial Growth Factors(VEGFs), Fibroblast Growth Factors (FGFs), Tumor Necrosis Factor-beta(TNF-beta), and Insulin-like Growth Factor-1 (IGF-1). Many of theseproteinaceous growth factors are available commercially or can beproduced recombinantly using techniques well known in the art.

Alternatively, expression systems comprising vectors, particularlyadenovirus vectors, incorporating genes encoding a variety ofbiomolecules can be dispersed in the invention PEA and PEUR co-polymercompositions and particles thereof for timed release delivery. Methodsof preparing such expression systems and vectors are well known in theart. For example, proteinaceous growth factors can be dispersed into theinvention bioactive compositions for administration of the growthfactors either to a desired body site for local delivery, by selectionof particles sized to form a co-polymer depot, or systemically, byselection of particles of a size that will enter the circulation. Growthfactors, such as VEGFs, PDGFs, FGF, NGF, and evolutionary andfunctionally related biologics, and angiogenic enzymes, such asthrombin, may also be used as bioactive agents in the invention.

Small molecule drugs are yet another category of bioactive agentssuitable for dispersion in the invention PEA and PEUR co-polymercompositions and in methods for delivery described herein. Such drugsinclude, for example, antimicrobials and anti-inflammatory agents aswell as certain healing promoters, such as, for example, vitamin A andsynthetic inhibitors of lipid peroxidation.

A variety of antibiotics can be dispersed as bioactive agents in theinvention PEA and PEUR co-polymer compositions to indirectly promotenatural healing processes by preventing or controlling infection.Suitable antibiotics include many classes, such as aminoglycosideantibiotics, quinolones or beta-lactams, such as cefalosporins, e.g.,ciprofloxacin, gentamycin, tobramycin, erythromycin, vancomycin,oxacillin, cloxacillin, methicillin, lincomycin, ampicillin, andcolistin. Suitable antibiotics have been described in the literature.

Suitable antimicrobials include, for example, Adriamycin PFS/RDF®(Pharmacia and Upjohn), Blenoxane® (Bristol-Myers SquibbOncology/Immunology), Cerubidine® (Bedford), Cosmegen® (Merck),DaunoXome® (NeXstar), Doxil® (Sequus), Doxorubicin Hydrochloride®(Astra), Idamycin® PFS (Pharmacia and Upjohn), Mithracin® (Bayer),Mitamycin® (Bristol-Myers Squibb Oncology/Immunology), Nipen®(SuperGen), Novantrone® (Immunex) and Rubex® (Bristol-Myers SquibbOncology/Immunology). In one embodiment, the peptide can be aglycopeptide. “Glycopeptide” refers to oligopeptide (e.g. heptapeptide)antibiotics, characterized by a multi-ring peptide core optionallysubstituted with saccharide groups, such as vancomycin.

Examples of glycopeptides included in this category of antimicrobialsmay be found in “Glycopeptides Classification, Occurrence, andDiscovery,” by Raymond C. Rao and Louise W. Crandall, (“Bioactive agentsand the Pharmaceutical Sciences” Volume 63, edited by RamakrishnanNagarajan, published by Marcal Dekker, Inc.). Additional examples ofglycopeptides are disclosed in U.S. Pat. Nos. 4,639,433; 4,643,987;4,497,802; 4,698,327, 5,591,714; 5,840,684; and 5,843,889; in EP 0 802199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589;WO 98/52592; and in J. Amer. Chem. Soc. (1996) 118: 13107-13108; J.Amer. Chem. Soc. (1997) 119:12041-12047; and J. Amer. Chem. Soc. (1994)116:4573-4590. Representative glycopeptides include those identified asA477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850,A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin,Balhimyein, Chloroorientiein, Chloropolysporin, Decaplanin,-demethylvancomycin, Eremomycin, Galacardin, Helvecardin, Izupeptin,Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721,MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653,Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin,UK-68597, UD-69542, UK-72051, Vancomycin, and the like. The term“glycopeptide” or “glycopeptide antibiotic” as used herein is alsointended to include the general class of glycopeptides disclosed aboveon which the sugar moiety is absent, i.e. the aglycone series ofglycopeptides. For example, removal of the disaccharide moiety appendedto the phenol on vancomycin by mild hydrolysis gives vancomycinaglycone. Also included within the scope of the term “glycopeptideantibiotics” are synthetic derivatives of the general class ofglycopeptides disclosed above, including alkylated and acylatedderivatives. Additionally, within the scope of this term areglycopeptides that have been further appended with additional saccharideresidues, especially aminoglycosides, in a manner similar tovancosamine.

The term “lipidated glycopeptide” refers specifically to thoseglycopeptide antibiotics that have been synthetically modified tocontain a lipid substituent. As used herein, the term “lipidsubstituent” refers to any substituent contains 5 or more carbon atoms,preferably, 10 to 40 carbon atoms. The lipid substituent may optionallycontain from 1 to 6 heteroatoms selected from halo, oxygen, nitrogen,sulfur, and phosphorous. Lipidated glycopeptide antibiotics are wellknown in the art. See, for example, in U.S. Pat. Nos. 5,840,684,5,843,889, 5,916,873, 5,919,756, 5,952,310, 5,977,062, 5,977,063, EP667, 353, WO 98/52589, WO 99/56760, WO 00/04044, WO 00/39156, thedisclosures of which are incorporated herein by reference in theirentirety.

Anti-inflammatory bioactive agents are also useful for dispersion ininvention PEA and PEUR co-polymer compositions and the methods ofdelivery disclosed herein. Depending on the body site and disease to betreated, such anti-inflammatory bioactive agents include, e.g.analgesics (e.g., NSAIDS and salicyclates), steroids, antirheumaticagents, gastrointestinal agents, gout preparations, hormones(glucocorticoids), nasal preparations, ophthalmic preparations, oticpreparations (e.g., antibiotic and steroid combinations), respiratoryagents, and skin & mucous membrane agents. See, Physician's DeskReference, 2005 Edition. Specifically, the anti-inflammatory agent caninclude dexamethasone, which is chemically designated as (11θ,16I)-9-fluro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione.Alternatively, the anti-inflammatory bioactive agent can be or includesirolimus (rapamycin), which is a triene macrolide antibiotic isolatedfrom Streptomyces hygroscopicus.

The polypeptide bioactive agents included in the invention compositionsand methods can also include “peptide mimetics.” Such peptide analogs,referred to herein as “peptide mimetics” or “peptidomimetics,” arecommonly used in the pharmaceutical industry with properties analogousto those of the template peptide (Fauchere, J. (1986) Adv. Bioactiveagent Res., 15:29; Veber and Freidinger (1985) TINS, p. 392; and Evanset al. (1987) J. Med. Chem., 30:1229) and are usually developed with theaid of computerized molecular modeling. Generally, peptidomimetics arestructurally similar to a paradigm polypeptide (i.e., a polypeptide thathas a biochemical property or pharmacological activity), but have one ormore peptide linkages optionally replaced by a linkage selected from thegroup consisting of: —CH₂NH—, —CH₂S—, CH₂—CH₂—, —CH═CH— (cis and trans),—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—, by methods known in the art andfurther described in the following references: Spatola, A. F. inChemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B.Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F.,Vega Data (March 1983), Vol. 1, Issue 3, “Peptide BackboneModifications” (general review); Morley, J. S., Trends. Pharm. Sci.,(1980) pp. 463-468 (general review); Hudson, D. et al., Int. J. Pept.Prot. Res., (1979) 14:177-185 (—CH₂NH—, CH₂CH₂—); Spatola, A. F. et al.,Life Sci., (1986) 38:1243-1249 (—CH₂—S—); Harm, M. M., J. Chem. Soc.Perkin Trans I (1982) 307-314 (—CH═CH—, cis and trans); Almquist, R. G.et al., J. Med. Chem., (1980) 23:2533 (—COCH₂—); Jennings-Whie, C. etal., Tetrahedron Lett., (1982) 23:2533 (—COCH₂—); Szelke, M. et al.,European Appin., EP 45665 (1982) CA: 97:39405 (1982) (—CH(OH)CH₂—);Holladay, M. W. et al., Tetrahedron Lett., (1983) 24:4401-4404(—C(OH)CH₂—); and Hruby, V. J., Life Sci., (1982) 31:189-199 (—CH₂—S—).Such peptide mimetics may have significant advantages over naturalpolypeptide embodiments, including, for example: more economicalproduction, greater chemical stability, enhanced pharmacologicalproperties (half-life, absorption, potency, efficacy, etc.), alteredspecificity (e.g., a broad-spectrum of biological activities), reducedantigenicity, and others.

Additionally, substitution of one or more amino acids within a peptide(e.g., with a D-Lysine in place of L-Lysine) may be used to generatemore stable peptides and peptides resistant to endogenous peptidases.Alternatively, the synthetic polypeptides covalently bound to thebiodegradable co-polymer, can also be prepared from D-amino acids,referred to as inverso peptides. When a peptide is assembled in theopposite direction of the native peptide sequence, it is referred to asa retro peptide. In general, polypeptides prepared from D-amino acidsare very stable to enzymatic hydrolysis. Many cases have been reportedof preserved biological activities for retro-inverso or partialretro-inverso polypeptides (U.S. Pat. No. 6,261,569 B1 and referencestherein; B. Fromme et al, Endocrinology (2003)144:3262-3269.

Any suitable and effective amount of the at least one bioactive agentcan be released with time from the invention compositions, includingthose in a biodegradable internal fixation device, stent, or dialysisshunt, or in a depot formed from particles thereof introduced in vivo.The suitable and effective amount of the bioactive agent will typicallydepend, e.g., on the specific PEA or PEUR co-polymer and type ofparticle or co-polymer/bioactive agent linkage, if present. Typically,up to about 100% of the bioactive agent(s) can be released from theinvention co-polymer in vivo. Specifically, up to about 90%, up to 75%,up to 50%, or up to 25% thereof can be released from the co-polymer.Factors that typically affect the release rate from the co-polymer arethe types of co-polymer/bioactive agent linkage, and the nature andamount of additional substances present in the formulation.

In addition to humans, the invention PEA and PEUR co-polymercompositions, as well as particles and surgical devices fabricatedtherefrom, are also intended for use in veterinary practice, including avariety of mammalian patients, such as pets (for example, cats, dogs,rabbits, and ferrets), farm animals (for example, swine, horses, mules,dairy and meat cattle) and race horses.

In one embodiment, the invention compositions, devices and methods ofadministration may release an “effective amount” of one or morebioactive agent(s). That is, an amount of a bioactive agent will beincorporated into the co-polymer thereof that will produce a sufficienttherapeutic or palliative response in order to prevent, reduce oreliminate symptoms. The exact amount necessary will vary, depending onthe subject to which the composition is being administered; the age andgeneral condition of the subject; the capacity of the subject's immunesystem, the degree of therapeutic or palliative response desired; theseverity of the condition being treated or investigated; the particularbioactive agent selected and the mode of administration of thecomposition, among other factors. An appropriate effective amount can bereadily determined by one of skill in the art. Thus, an “effectiveamount” will fall in a relatively broad range that can be determinedthrough routine trials. For example, for purposes of the presentinvention, an effective amount will typically range from about 1 μg toabout 100 mg, for example from about 5 μg to about 1 mg, or about 10 μgto about 500 μg of the bioactive agent delivered.

The following examples are meant to illustrate, but not to limit theinvention.

Preparation of Invention co-PEAs Based on bis-(α-aminoacid)-diol-diesters

Example 1

This example illustrates preparation ofco-poly-4-[Leu(DAS)_(0.75)-Leu(6)_(0.25)] (Compound #2, of Table 1.),which is described by structural formula (I), wherein m=0.75, p=0.25,R¹═R²═(CH₂)₄, R³═R⁴=iso-butyl, R⁵═(CH₂)₆, and R⁶=formula (III).

Triethylamine (NEt₃) (9.67 mL, 0.069 mole) was added to a mixture ofdi-p-toluenesulfonic acid salt ofbis-(L-leucine)-1,4:3,6-dianhydrosorbitol diester (16.9577 g, 0.024mole); di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (5.4320 g, 0.008 mole); and di-p-nitrophenyl adipate (12.2482 g,0.032 mole) in dimethylformamide (DMF) (16.61 mL) (total volume of DMFand NEt₃ is 26.28 mL, concentration of 1.2 mol/L by di-p-nitrophenyladipate) at room temperature. Afterwards, the temperature was increasedto about 80° C. and stirred for about 24 hours. The viscous reactionsolution was cooled to room temperature, diluted with DMF (123.72 mL)(total volume of DMF and NEt₃ is 150 mL, concentration of 10% (w/v)).Acetic anhydride (0.567 mL, 0.006 mole) was added and stirred for about16 hours. The reaction solution was thoroughly washed with water andsodium bicarbonate (1% w/v). For final purification, the co-polymerobtained was dissolved in ethanol (150 mL, 10% w/v). The solution wasprecipitated in ethyl acetate (1.5 L). Precipitation in the ethylacetate was repeated until a negative test on p-nitrophenol (aby-product of the polycondensation) was obtained, normally 1-2 times.

The obtained co-polymer was dissolved in ethanol, filtered and dried atabout 65° C. under reduced pressure until dry. Yield was 80-90%,M_(w)=211,900 (Gel Permeation Chromatography (GPC) inN,N-dimethylacetamide (DMAc)).

For testing of mechanical properties, as shown in Table 1 above andTable 2 below, dumbbell-shaped films (4×1.6 cm) were cast fromchloroform solution, with average thickness of 0.125 mm and subjected totensile testing on tensile strength machine (Chatillon TDC200)integrated with a PC (Nexygen FM software) at a crosshead speed of 100mm/min Glass transition temperatures were determined by DifferentialScanning calorimetry (DSC). Measurements were taken from second heating,heating rate 10° C./min

Example 2

This example illustrates preparation ofpoly-4-[L-Leu(DAS)_(0.45)-L-Leu(6)_(0.55)] (Compound #3, of Table 1.),which is described by structural formula (I) wherein m=0.45, q=0.55,R¹═R²═(CH₂)₄, R³═R⁴=iso-butyl, R⁵═(CH₂)₆, R⁶=formula (III).

Triethylamine (9.85 mL, 0.071 mole) was added to a mixture ofdi-p-toluenesulfonic acid salt ofbis-(L-leucine)-1,4:3,6-dianhydrosorbitol diester (10.3574 g, 0.014mole); di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (12.1651 g, 0.018 mole); and di-p-nitrophenyl adipate (12.4681g, 0.032 mole) in DMF (16.91 mL) (total volume of DMF and NEt₃ is 26.76mL, concentration of 1.2 mol/L by di-p-nitrophenyl adipate) at roomtemperature. Afterwards, the temperature was increased to about 80° C.and stirred for about 24 hours. The viscous reaction solution was cooledto room temperature, diluted with DMF (123.24 mL) (total volume of DMFand NEt₃ is 150 mL, concentration of 10% (w/v)). Acetic anhydride (0.567mL, 0.006 mole) was added and stirred for about 16 hours. The reactionsolution was thoroughly washed with water and sodium bicarbonate (1%w/v). For final purification, the co-polymer obtained was dissolved inethanol (150 mL, 10% w/v). The solution was precipitated in ethylacetate (1.5 L). Precipitation in ethyl acetate was repeated until anegative test on p-nitrophenol (a by-product of the polycondensation)was obtained, normally 1-2 times.

The obtained co-polymer was dissolved in ethanol, filtered and dried atabout 65° C. under reduced pressure until dry. Yield was 80-90%,M_(w)=210,200 (GPC in DMAc).

Example 3

This example illustrates preparation ofpoly-4-[L-Leu(DAS)_(0.20)-L-Leu(6)_(0.80)] (Compound #4, of Table 1.),which is described by structural formula (I), wherein m=0.20, q=0.80,R¹═R²═(CH₂)₄, R³═R⁴=iso-butyl, R⁵═(CH₂)₆, R⁶=formula (III).

Triethylamine (9.99 mL, 0.072 mole) was added to a mixture ofdi-p-toluenesulfonic acid salt ofbis-(L-leucine)-1,4:3,6-dianhydrosorbitol diester (4.6732 g, 0.007mole); di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (17.9636 g, 0.026 mole); and di-p-nitrophenyl adipate (12.6576g, 0.033 mole) in DMF (17.17 mL) (total volume of DMF and NEt₃ is 27.16mL, concentration of 1.2 mol/L by di-p-nitrophenyl adipate) at roomtemperature. Afterwards, the temperature was increased to about 80° C.and stirred for about 24 hours. The viscous reaction solution was cooledto room temperature, diluted with DMF (122.84 mL) (total volume of DMFand NEt₃ is 150 mL, concentration of 10% (w/v)). Acetic anhydride (0.567mL, 0.006 mole) was added and stirred for about 16 hours. The reactionsolution was thoroughly washed with water and sodium bicarbonate (1%w/v). For final purification, the co-polymer obtained was dissolved inethanol (150 mL, 10% w/v). The solution was precipitated in ethylacetate (1.5 L). Precipitation in ethyl acetate was repeated until anegative test on p-nitrophenol (a by-product of the polycondensation)was obtained, normally 1-2 times.

The obtained co-polymer was dissolved in ethanol, filtered and dried atabout 65° C. under reduced pressure until dry. Yield was 80-90%,M_(w)=199,200 (GPC in DMAc).

Example 4

This example illustrates preparation ofpoly-4-[L-Phe(DAS)_(0.75)-L-Phe(4)_(0.25)] (Compound #2, of Table 2),which is described by structural formula (I) wherein m=0.20, q=0.80,R¹═R²═(CH₂)₄, R³═R⁴═CH₂(C₆H₅), R⁵═(CH₂)₄, R⁶=formula (III).

Triethylamine (8.57 mL, 0.061 mole) was added to the mixture ofdi-p-toluenesulfonic acid salt ofbis-(L-phenylalanine)-1,4:3,6-dianhydrosorbitol diester (16.4557 g,0.021 mole); di-p-toluenesulfonic acid salt ofbis-(L-phenylalanine)-1,4-butylene diester (5.0937 g, 0.007 mole); anddi-p-nitrophenyl adipate (10.8554 g, 0.028 mole) in dimethylformamide(14.72 mL) (total volume of DMF and NEt₃ is 23.30 mL, concentration of1.2 mol/L by di-p-nitrophenyl adipate) at room temperature. Afterwards,the temperature was increased to about 80° C. and stirred for about 24hours. The viscous reaction solution was cooled to room temperature,diluted with DMF (126.70 mL) (total volume of DMF and NEt₃ is 150 mL,concentration of 10% (w/v)). Acetic anhydride (0.567 mL, 0.006 mole) wasadded and stirred for about 16 hours. The reaction solution wasthoroughly washed with water and sodium bicarbonate (1% w/v). For finalpurification, the co-polymer obtained was dissolved in THF (150 mL, 10%w/v). The solution was precipitated in ethyl acetate (1.5 L).Precipitation in ethyl acetate was repeated until a negative test onp-nitrophenol (a by-product of the polycondensation) was obtained,normally 1-2 times.

The obtained co-polymer was dissolved in THF, filtered and dried atabout 65° C. under reduced pressure until dry. Yield was 80-90%,M_(w)=75,200 (GPC in DMAc).

Preparation of Invention bis-(α-amino acid)-Based PEURs

Example 5

This example illustrates preparation ofpoly-3-[L-Leu(DAS)_(0.15)-L-Leu(6)_(0.60)-(L-Lys(Bn)_(0.25)] (Compound#3, Table 2), which is described by structural formula (V) whereinp=0.6, m=0.15, q=0.25, R⁸═R⁹═(CH₂)₃, R³═R⁴=iso-butyl, R⁸═(CH₂)₆,R⁹=formula III, R⁷═CH₂(C₆H₅). (see scheme 2 below)

Triethylamine (10.32 mL, 0.0742 mole) was added to a mixture ofdi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(11.7304 g, 0.0202 mole), di-p-toluenesulfonic acid salt ofbis-(L-leucine)-1,4:3,6-dianhydrosorbitol diester (3.5843 g, 0.0050mole), di-p-toluenesulfonic acid salt of L-lysine benzyl ester (4.8879g, 0.0084 mole), and propyl biscarbonate (13.6793 g, 0.0336 mole) in DMF(17.73 mL) (total volume of DMF and NEt₃ is 28.05 mL, concentration of1.2 mol/L by the propyl biscarbonate) at room temperature. Afterwards,the temperature was increased to about 80° C. and stirred for about 24hours. The viscous reaction solution was cooled to room temperature,diluted with DMF (121.95 mL) (total volume of DMF and NEt₃ is 150 mL,concentration of 10% (w/v)). Acetic anhydride (0.567 mL) was added andstirred for about 16 hours. The reaction solution was thoroughly washedwith water and sodium bicarbonate (1% w/v).

For final purification, the co-polymer obtained was dissolved in acetone(150 mL, 10% w/v). The solution was precipitated in ethyl ether (1.5 L).Precipitation in ethyl ether was repeated until a negative test onp-nitrophenol (a by-product of the polycondensation) was obtained,normally 1-2 times. The obtained co-polymer was dissolved in acetone,filtered and dried at about 65° C. under reduced pressure until dry.Yield was 80-90%, M_(w)=78,000 (GPC in DMAc).

Preparation of Unsaturated Co-PEAs

Example 6

Preparation ofco-poly-[(8)_(0.75)-(Fum)_(0.25)]-[L-Leu(6)_(0.50)-L-Leu(DAS)_(0.50)](Compound #4, Table 1), which is described by formula (I) whereinm=0.50, q=0.50, R¹═(CH₂)₈, R²═(CH₂)₈-25% and (—CH═CH—)-25%.R³═R⁴=iso-butyl, R⁵═(CH₂)₆, R⁶=formula (III)).

Triethylamine (2.84 mL, 20.4 mmole) was added to the mixture ofdi-p-toluenesulfonic acid salt ofbis-(L-Leucine)-1,4:3,6-dianhydrosorbitol diester (3.5619 g, 4.968mmole); di-p-toluenesulfonic acid salt ofbis-(L-Leucine)-1,6-hexanediol-diester (3.4229 g, 4.968 mmole);di-p-nitrophenyl-fumarate (0.8901 g, 2.4844 mmole) and di-p-nitrophenylsebacinate (3.3124 g, 7.453 mmole) in DMF (5.44 mL) (total volume of DMFand NEt₃ is 23.30 mL, concentration of 1.2 mol/L by di-p-nitrophenyladipate) at room temperature. Afterwards, the temperature was increasedto about 52° C. and stirred for about 8 hours. The viscous reactionsolution was cooled to room temperature, diluted with DMF (40 mL) (totalvolume of DMF and NEt₃ is 50 mL, concentration of 10% (w/v)). Aceticanhydride (0.25 mL) was added and stirred for about 3 hours. The viscousco-polymer solution was precipitated in water, washed thoroughly withwater and sodium bicarbonate (1% w/v) solution. For final purification,the co-polymer obtained was dissolved in ethanol (150 mL, 10% w/v). Thesolution was precipitated in ethyl acetate (1.5 L). Yield, 65%,M_(w)=84,000 (GPC in DMAc).

Example 7

The following example illustrates the mechanical and physico-chemicalproperties of PEAs and PEURs based on different feed ratios of theDAS-containing co-monomer. The relative feed ratios for fabrication ofthe co-polymers and the properties obtained are as shown in Table 2below.

TABLE 2 Modulus of Compound M_(w) ^(a)) M_(n) ^(a)) Tg^(b)) % Elasticity(#), composition ×10⁻³ ×10⁻³ M_(w)/M_(n) ^(a)) [° C.] Elongation [MPa](1), 4-Leu(6)_(0.75)Lys(Bn)_(0.25) 223 135 1.65 45 446 462 (2),4-Phe(DAS)_(0.75)Phe(4)_(0.25) 175 100 1.75 90 13 2600 (3),3-Leu(DAS)_(0.15)Leu(6)_(0.60) 78 52 1.50 32 181 425    Lys(Bn)_(0.25)(4), (8)_(0.75)-(Fum)_(0.25)- 84 43 1.95 69 4 1302   Leu(6)_(0.50)-Leu(DAS)_(0.50) ^(a))GPC Measurements were carried out inDMAc, (PS). ^(b))Tg was taken from second heating curve with heatingrate of 10 C./min by DSC.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications might be made while remainingwithin the spirit and scope of the invention.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A biodegradable, biocompatible surgical devicecomprising a co-polymer composition comprising at least one or a blendof the following co-polymers: a PEA having a chemical structuredescribed by general structural formula (I):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and wherein n is about 5 to about 100; and wherein R¹ is independentlyselected from the group consisting of (C₂-C₂₀) alkylene, (C₂-C₂₀)alkenylene, and combinations thereof; R³s and R⁴s in a single co-monomerm or p, respectively, are independently selected from the groupconsisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl,(C₆-C₁₀) aryl (C₁-C₆) alkyl and —(CH₂)₂S(CH₃); R⁵ is selected frombicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula(II); and

R⁶ is selected from the group consisting of (C₂-C₂₀) alkylene, (C₂-C₂₀)alkenylene or alkyloxy; or a PEA having a chemical structure describedby general structural formula (III):

wherein m is about 0.01 to about 0.99; p is about 0.99 to about 0.01;and q is about 0.99 to 0.01; and wherein n is about 5 to about 100; andwherein R¹ is independently selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and combinations thereof; R³sand R⁴s in a single co-monomer m or p, respectively, are independentlyselected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl and —(CH₂)₂S(CH₃);R⁵ is selected from bicyclic-fragments of 1,4:3,6-dianhydrohexitols ofstructural formula (II); R⁶ is selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene or alkyloxy; R⁷ is hydrogen,(C₆-C₁₀) aryl (C₁-C₆) alkyl or a protecting group; and R⁸ isindependently (C₁-C₂₀) alkyl or (C₂-C₂₀) alkenyl.
 2. The device of claim1 wherein at least one of the R³s or R⁴s in a co-polymer molecule is—CH₂Ph.
 3. The device of claim 1, wherein all of the R³s and R⁴s areselected from hydrogen, CH₂—CH(CH₃)₂, —CH₃, —CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃,—CH₂—C₆H₅, —(CH₂)₄—NH₂, or —(CH₂)₂SCH₃.
 4. The device of claim 1,wherein at least one of R¹ and R² is selected from —CH₂—CH═CH—CH₂,—(CH₂)₄—, —(CH₂)₆—, and —(CH₂)₈—.
 5. The device of claim 1, wherein atleast one R⁵ and R⁶ is —CH₂—CH═CH—CH₂—.
 6. The device of claim 1,wherein the 1,4:3,6-dianhydrohexitol is derived from D-glucitol,D-mannitol, or L-iditol.
 7. The device of claim 1, wherein the1,4:3,6-dianhydrohexitol is 1,4:3,6-dianhydrosorbitol (DAS).
 8. Thedevice of claim 1, wherein the R⁸ is independently (C₃-C₆) alkyl or(C₃-C₆) alkenyl.
 9. The device of claim 1, wherein the R⁸ is —(CH₂)₄—.10. The device of claim 1 wherein the composition further comprises atleast one bioactive agent dispersed in the co-polymer.
 11. The device ofclaim 10 wherein the bioactive agent is released in a controlled mannerfrom the surgical device under physiological conditions.
 12. The deviceof claim 10 wherein the bioactive agent is released over a time fromabout two days to about six years.
 13. The device of claim 1 wherein thesurgical device is a vascular stent or dialysis shunt.
 14. The device ofclaim 1 wherein the surgical device is an internal fixation device. 15.The device of claim 14 wherein the internal fixation device is asurgical suture.
 16. The device of claim 14 wherein the internalfixation device is a surgical screw.
 17. The device of claim 14 whereinthe internal fixation device is an implantable plate.
 18. The device ofclaim 14 wherein the internal fixation device is an implantable rod.